Studies have shown that glaucoma is the second leading cause of blindness in the United States [Leske M C. The epidemiology of open-angle glaucoma: a review. Am J Epidemiology 1983; 118: 166-191]. The pathologic correlate of glaucoma is the progressive degeneration of retinal ganglion cells (RGC) and their axons which form the optic nerve.
The classification of glaucoma includes the following different types: primary angle-closure glaucoma, secondary open-angle glaucoma, steroid-induced glaucoma, traumatic glaucoma, pigmentary dispersion syndrome, pseudoexfoliation syndrome, secondary angle-closure glaucoma, neovascular glaucoma, uveitis and glaucoma and other non further specified eye pathologies.
Similarly, macular degeneration is a condition involving a pathology of the retina which has also been attributed to the occurrence of β-amyloid and leads to a progressive loss of vision, leading finally to blindness.
In the past, the definition of glaucoma included an elevation in the intraocular pressure (IOP) over a normal range. However, many individuals with clearly elevated IOP do not develop glaucoma, and up to 50% of patients with glaucoma do not have an increased IOP.
Currently available medications for the treatment of glaucoma belong to several pharmacological classes, including β-adrenergic blockers, cholinergic agonists, carbonic anhydrase inhibitors, and alpha2 agonists. All operate under a mechanism whereby the IOP is lowered. These existing therapies are typically administered as eye drops. Hyperosmotics may be administered intravenously for emergency treatment. In addition, laser therapy and surgical approaches are applied in special cases.
Irrespective of therapy, after 20 years of follow-up in glaucoma patients, glaucoma-related blindness will have reached 27% in at least one eye and 9% in both eyes [Hattenhauer M G, Johnson D H, Ing H H, et al. The probability of blindness from open-angle glaucoma. Ophthalmology 1998; 105: 2099-2104]. Thus, there exists a significant unmet medical need for alternative treatment strategies. Particularly for patients with progressive glaucomatous damage under normalized IOP, a therapy focusing on degenerating retinal ganglion cells is needed.
There are different theories regarding the cause for the degeneration of the retinal ganglion cells including mechanical, vascular and excitotoxic mechanisms. Only recently, β-amyloid (Aβ) has been found to co-localize with dying retinal ganglion cells [McKinnon S J. Glaucoma: Ocular Alzheimer's disease? Front Biosci. 2003; 8: 1140-1156; Yoneda S, Hara H, Hirata A, Fukushima M, Inomata Y, Tanihara H. Vitreous fluid levels of beta-amyloid(1-42) and tau in patients with retinal diseases. Jpn J Ophthalmol. 2005; 49(2): 106-108]. Animal studies demonstrate that, particularly, the soluble Aβ1-42 peptide oligomers are very potent toxins for retinal ganglion cells [Dahlgren K N, Manelli A M, Stine W B Jr, Baker L K, Krafft G A, LaDu M J. Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem. 2002; 277(35): 32046-32053; Guo L, Salt T E, Luong V, Wood N, Cheung W, Maass A, Ferrari G, Russo-Marie F, Sillito A M, Cheetham M E, Moss S E, Fitzke F W, Cordeiro F. Targeting amyloid-β in glaucoma treatment. PNAS 2007; 104 (33): 13444-13449].
Multiple potential treatments targeting Aβ are under development. The common mechanism of these approaches is to counteract the detrimental effects of Aβ, either by preventing its formation (e.g. APP secretase inhibitors), by neutralizing Aβ through antibodies, or by interfering with Aβ aggregation. The latter mechanism is of increasing interest within the scientific community since data from animal models clearly show beneficial effects of Aβ aggregation inhibitors or Aβ aggregation modulators on Aβ-induced neurotoxicity.
Inhibition of neurotoxic Aβ aggregation species has been shown to reduce glaucomatous degeneration of retinal ganglion cells [Guo, et al., PANS 2007, 13444]. The inhibitors used in these animal experiments were Congo red and Aβ antibodies. These agents are pharmacological research tools only and are not appropriate for treatment of humans for various reasons.
It would be an advantage to provide novel methods for the prevention and treatment of ocular disorders, in particular glaucoma and macular degeneration, and pharmaceutical compositions for effecting such prevention and treatment thereof. According to the current scientific understanding, Aβ aggregation inhibitors or Aβ aggregation modulators are administered continuously over long periods of time to cause a therapeutically relevant neuroprotective effect. Interruption of the therapy—even for a short period only—is understood to lead to the situation that, in the absence of the inhibitor/modulator, neurotoxic aggregation immediately restarts and the disease progresses (potentially even more aggressively then before). The same paradigm is postulated for the therapy of other Aβ-associated diseases as mentioned above.
Moreover, treatment of Aβ-associated eye conditions, such as glaucoma or macular degeneration, often requires dosage routes involving uncomfortable steps, such as intravitreal injections. Accordingly, there is a need to improve patient compliance and general wellbeing.
It would be a clear advantage for patients if the neuroprotective effects could be achieved by an interval therapy characterized by a first effective dose followed by “booster” doses with the possibility of drug-free periods in between, rather than by a strictly continuous dosage regimen. Of course, such an dosage schedule should nonetheless also ensure the best possible clinical outcome of therapy.
PCT International Application No. PCT/EP2008/006888 discloses that Aβ aggregation modulators may produce a therapeutically relevant neuroprotective effect in the treatment of glaucoma.
With the instant invention, it has been discovered that interval therapy employing such Aβ aggregation modulators may be an effective approach for the treatment of glaucoma and macular degeneration.
Moreover, it has been determined that intervallic treatment may prevent recurrence of glaucoma in patients with sufficient or stable treatment effects through administering a reduced dose of an Aβ aggregation modulator. A benefit associated with such treatment is a significantly reduced drug exposure, in particular reduced chronic exposure while the therapeutic effect is still sufficient. Also, it increases convenience of dosage for patients and thereby positively influences compliance.
Additional needs in the art which are addressed by the invention will become apparent hereinafter, and still further needs will be apparent to one skilled in the art.